Gene expression signatures correlate with survival of patients with head and neck cancer treated with platinum-based regimens

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 4430 Both the nucleotide excision repair (NER) pathway and glutathione S-transferase (GSTP1), a phase II metabolic enzyme, have independently been implicated as important predictors of responsiveness to platinum-based chemotherapy regimens and patient outcome in a variety of cancers. Here, we evaluated the association of mRNA expression profiles in both of these pathways as well as other DNA repair and cell cycle control pathways on survival in formalin-fixed paraffin embedded (FFPE) primary tumor and adjacent tissue samples from 96 patients with head and neck squamous cell carcinoma (HNSCC). All patients were treated with carboplatin or cisplatin, either alone or in combination with radiation or other agents. A panel of 128 genes was evaluated using a customized DASL assay on the Illumina Beadstation GX. The mean age of HNSCC diagnosis among these patients was 56.1 years, the median follow-up time was 834 days and a total of 25 deaths due to disease progression were observed. An important aspect of expression profile analysis is the characterization of relationships among multiple profiles on the basis of similarities. Using a graph-theoretic approach to identify patterns of gene expression, several interesting associations were observed. A common over-expressed gene profile consisting of 16 genes was detected in a subset of cases (n=21). These simultaneously most highly expressed genes in cancers of the oral cavity and pharynx were associated with a reduced survival of <500 days. The 16 genes associated with this reduced survival profile were from the NER, base excision repair and mismatch repair families. GSTP1 as well as three cell cycle control genes were also predictive of reduced survival. Interestingly, males were overrepresented in this subgroup of cases compared to the overall study population (7:1 vs. 4:1). Additionally, the presence or absence of this over-expressed gene panel was able to differentiate short and long term survival in oral cavity and pharyngeal cancer cases with 64% sensitivity and 80% specificity. The identification of gene expression profiles that can predict survival outcomes associated with platinum-based therapies provides an opportunity to evaluate the role of genes involved in DNA repair and response to treatment as well as to predict and potentially improve the efficacy of therapeutic approaches. Supported in part by NIH 1P50 CA097190.